Our program focuses on the determinants of cardiac rhythm and arrhythmias in the young. Our hypothesis is that the expression of electrophysiologic function in the young is influenced by the autonomic nervous system and the electrophysiologic properties of the heart in ways that differ importantly from the adult, and that require our in depth understanding if we are to prevent and treat disorders of the heart beat. Hence, we intend to study the neonatal, young and adult animal. Our approach is multifaceted in that electrophysiological, biophysical, biochemical, pharmacological, and cell culture techniques are used in studies of intact animals, isolated tissues, single cells and subcellular components. Although arrhythmogenesis in general can be thought of as encompassing abnormalities of impulse initiation and/or conduction, our intent in this five-year period is to concentrate on impulse initiation and its relationship to repolarization. The projects in the Program stress the study of electrophysiologic properties of intact animals and isolated tissues, ionic determinants of impulse initiation studied in the above models (Project A) and in single myocytes and cultured cells, and receptor-effector coupling. The Cores provide support services, and cell disaggregation and tissue culture. Although our overall approach includes the adult as a major reference population, the most intensive area of investigation is centered on the neonate and young. The significance of these studies is that they are geared to the young age group as a unique population in which rhythm and arrhythmias truly differ in their genesis and autonomic modulation from the adult. Using the information obtained we not only shall improve our understanding of the mechanisms responsible for normal rhythm and arrhythmias but can design and seek new means for the prevention and treatment of arrhythmias.